Project Summary The goal of this Center of Biomedical Research Excellence is to continue our efforts to develop molecular approaches for probing biology, to discover and apply new chemical biology tools for the study of biological pathways associated with disease, and to develop computational approaches for understanding small molecule interactions with complex macromolecular targets. With core strengths in synthesis, biochemistry, engineering and biology, our scientific team will develop new chemical biology tools for understanding the cellular and molecular mechanisms that bacterial pathogens use to survive and replicate inside host cells, new chemical tools and nucleotide analogs to understand the regulation of mRNA demethylation by a ?methyl eraser? enzyme and its dysregulation in human cancer, molecularly-defined nanoparticle adjuvants that yield specific immune responses in the lung to advance inhalable vaccine development, and computational approaches to elucidate the mechanisms by which small molecules regulate the structure and function of virus capsids. COBRE funding will be used to recruit two new faculty members who will complement the existing strengths of our center, which will be expanded through competitive pilot grants. In years 4 and 5 of the COBRE, five two- year replacement projects will be funded. Collaboration and resource sharing in the Delaware and national IDeA network will be critical for maximizing our research capacity, core facilities and mentoring network. In Phase II, this COBRE continue to develop unique core facilities that facilitates high throughput synthesis, purification, screening and analysis of chemical probes. Building on the infrastructure established in Phase I, we will support a core facility in Analytical Chemistry, which will provide support for critical core facilities in mass spectrometry, solution NMR and kinetic analysis. The center will also support a Synthesis and Discovery core facility, which will provide custom synthesis services and instrumentation and infrastructure for small molecule synthesis, high throughput catalyst discovery, parallel synthesis, computation and microscopy.